Despite extraordinary recent progress in HIV/AIDS research and management, developing a multi-platform approach of prevention, vaccine, and therapeutic strategies remains essential to stem the tide of the pandemic. Vaccines and therapeutics traditionally focus on eliciting a slow but specific adaptive immune response. However, this response appears to be too little and too late to effectively control infection. Therefore, a better understanding of how to maximally mobilize all arms of the immune system is crucial. Natural killer cells are a unique lineage of innate lymphocytes that rapidly and vigorously respond to the early stages of HIV infection. due to the difficulty of studying their diversity and This is achieved by a signaling paradigm fundamentally different from all other immune cells. NK cell activation status is controlled by the integration of signals from a mosaic of activating and inhibitory receptors that recognize either general features of infected cells or specific viral proteins. Different combinations of receptors can be present on each NK cell and directly correlate with a cell's functional status. However, NK cells have traditionally been regarded as a homogenous and nonspecific population because their multifactorial recognition mechanism has been difficult to study due to the technological limitations of flow cytometry, which allows interrogation of only 12-18 markers at once. Here, we propose using a novel technology, mass cytometry (also known as cytometry by time-of-flight or CyTOF), to better understand the phenotypic and functional diversity of NK cells responding to HIV infection. We hypothesize that specific subpopulations of NK cells respond to HIV-infected cells through distinct receptor interactions. Using mass cytometry, we will detect receptors involved and functions induced during NK cell recognition and killing of HIV-infected CD4 T cells using a robust in vitro viral suppression assay. We will then determine the mechanisms by which NK cell subpopulations recognize and respond to HIV-infected cells using a variety of well-established molecular and cellular techniques, including siRNA knockdown, p815 redirected lysis assays, confocal imaging, and fluorescence cytometry sorting. Finally, we will drive an evolutionary battle between NK cells and HIV in order to identify the critical features of the NK cell response that the virus evades. We will therefore identify those features most critical for NK cell-mediated recognition, as well as pathways that could prevent viral escape from the NK cell response. This work will lay the groundwork for a new understanding of the potential for NK cells to control HIV, with a promise to reveal specific pathways that will advance innovative, mechanism-based vaccine and therapeutic strategies.